Project Summary/Abstract: Research Project (A) Our long-term goal is to understand the impact of hormones on the neural mechanisms underpinning specific maladaptive processes associated with psychopathology, which will facilitate the development of improved treatment strategies. Estimates indicate that over 20% of American adolescents suffer from serious psychopathology, including stress, mood, anxiety, and behavioral disorders. Patients with these disorders show deficits in emotion regulation, part of the cognitive control construct within the Research Domain Criteria framework. Importantly, the prevalence rates of these psychiatric disorders increase during the transition from childhood to adolescence, coinciding with drastic pubertal changes in hormone levels. Furthermore, biological sex has been shown to substantially influence both hormone functioning and the prevalence of these disorders. Thus, our objective in this application is to identify the role of testosterone (T) and cortisol (C) reactivity in modulating neural activity associated with emotion regulation in male and female adolescents without and with psychopathology (i.e., emotion regulation issues). Consistent with the NIH?s mission to reduce the burden of mental disorders, the proposed work will yield a better understanding of the biological mechanisms underpinning emotion regulation, and thereby support the development of new and improved interventions for adolescents with psychopathology. The current proposal aims specifically to (i) clarify the extent to which T reactivity modulates emotion regulation and neural function in youth with psychopathology (i.e., emotion regulation issues) relative to typically-developing (TD) youth, and the degree by which pubertal status mediates this relationship in each group; (ii) determine the role of C reactivity in emotion regulation and neural function in youth with psychopathology and TD youth, and the degree to which pubertal status mediates these relationships and; (iii) identify the role of biological sex in modulating T and C reactivity in the context of emotion regulation in youth with psychopathology relative to TD youth. These aims will be accomplished by recruiting 238 adolescent participants (aged 9-15 years; half female; half community controls), including 119 adolescent patients with psychopathology (i.e., emotion regulation issues) from an academic medical center?s psychiatry clinic. Participants will complete an fMRI paradigm assessing emotion regulation following a social challenge paradigm designed to elicit a T response. Pilot data indicates that increased T response improves emotion regulation in healthy youth, but impairs it in youth with psychopathology. Further, the role of C in these disorders is unknown. It is anticipated that the proposed study will show the extent to which T and C reactivity each impact behavior and neural activity related to emotion regulation in youth with psychopathology, particularly across pubertal development. Additionally, sex differences in these relationships will be examined. As current intervention strategies for psychopathology do not consider hormonal mechanisms, these data will be important in the development of novel treatment modalities.